The present invention relates to synthetic vascular grafts, and in particular, to multi-zone and multifunctional synthetic vascular grafts, thereby improving the biocompatibility and long term patency of synthetic vascular grafts.
Synthetic vascular grafts form an important therapeutic component to replace diseased arteries and thus save an important organ, limb, or in many cases, the life of the patient. Most synthetic vascular grafts are tubular structures that geometrically mimic the native blood vessel that it is meant to replace. While a natural blood vessel consists of many layers intimately joined together, synthetic vascular conduits are of a monolithic construction consisting of only one layer. These tubular structures are generally fabricated out of knitted or woven Dacron polyester yams or they are extruded polyurethane tubes or extruded PTFE tubes with defined porosities in the wall of the extruded tube. It is important to recognize that in the case of structures that are woven or knitted from Dacron polyester yam or fabricated from extruded PTFE tubes with porous walls, the porous nature of these structures is both a benefit and a detraction. The porous walls of these devices are designed to promote tissue in-growth under the proper environment, thus integrating the graft into the surrounding tissue. Studies by other investigators have resulted in currently marketed products that have a wall pore size of approximately 20 xcexcm. The porous walls also result in blood leakage unless they are sealed. Several approaches are used to seal these grafts. One approach is to pre-clot the graft with the patient""s blood. A second method uses impregnation of the graft with pure bovine collagen. The bovine collagen, which is similar to human collagen, a member of the basement membrane family of human tissue, promotes clotting and thus prevents leaks. A third method uses a topical application of the blood coagulant, thrombin, mixed with cryoprecipitate. While the primary purpose of these coatings is to seal the exterior of porous grafts, a further objective in all these methods is to improve the biocompatibility of the grafts.
All the approaches described above suffer some basic disadvantages that prevent the use of these types of coatings in fabricating small diameter synthetic grafts for replacing diseased vessels, particularly in peripheral applications below the knee and in coronary applications. While these problems also exist in larger diameter synthetic grafts such as those with internal diameter 6 mm and above, the problem is particularly acute in small diameter conduits. For the purpose of this invention, small diameter synthetic vascular conduits are defined as those with internal diameter xe2x89xa65 mm.
The specific problem associated with all the approaches described so far is their inability to maintain long-term patency of the graft. Over time the internal diameter of these grafts continues to decrease, eventually shutting off the blood flow. This phenomenon can occur in periods as short as three weeks or may occur over a period of several years. The problem occurs because the grafts prepared by the three methods described above create a reactive surface on the inner lumen of the graft, leading to several biological events including thrombosis, platelet aggregation leading to the formation of white thrombus, and proliferation of smooth muscle cells leading to intimal thickening and a reduction in the lumen diameter. The latter problem of smooth muscle cell proliferation is particularly problematic at the anastomosis site where the grafts are sutured to the native vessel.
Studies by Wagner, Tiffany, Thompson, Shultz, and Johnson of the Department of Surgery at the University of Pittsburgh, reported in Transactions, Society of Biomaterials, 1994, have shown that thrombin, topically applied to the external surface of the graft retains its activity in excess of 300 days and that this activity is resistant to both heparin and hirudin, which are potent anti-coagulants. Any migration of these thrombotic agents can have disastrous consequences by promoting thrombosis and plugging the vascular conduit being repaired.
Several approaches have been tried in an effort to maintain anti-coagulant behavior of the interior surface of the graft and ensure long-term patency. The inner surface of native blood vessels are lined with a layer of endothelial cells that maintain the surface in a non-thrombogenic state except when there is injury to the vasculature. In order to mimic this process, there has been an effort to grow endothelial cells on the surface of synthetic grafts. However, endothelial cells are expensive and difficult to grow on synthetic surfaces. Furthermore, there is no guarantee that the presence of endothelial cells will necessarily improve the patency of small caliber vascular conduits. Because collagen and fibronectin are known to promote the growth of many human cells including endothelial cells, the first attempt has been to coat the interior surface of these synthetic grafts with collagen, fibronectin, or a mixture of these two components.
For example, Sorin Biomedical of Italy markets a Dacron vascular graft that has been impregnated with bovine collagen. While this technique works for larger diameter grafts with internal diameters of xe2x89xa76 mm, this coating is unsuccessful with smaller diameter conduits. While collagen coating can and often does promote the growth of endothelial cells on the surface, it does nothing to prevent or retard intimal hyperplasia. Guidoin et al, reporting in ASAIO Journal Nov-Dec; 42, 1996, compared collagen impregnated grafts with pre-clotted grafts used as controls when implanted in canine models for periods ranging from one month to six months. While the collagen impregnated grafts showed a presence of endothelial cells on the inner lumen after a 30 day implantation, they found that the collagen impregnated grafts had a significantly higher wall thickness for most of the implantation period when compared with the pre-clotted grafts. The authors concluded that collagen impregnated polyester prosthesis cannot be recommended as small diameter blood conduits.
Clapper et al, reporting in Symposium, Society for Biomaterials, 1994, used a mixture of fibronectin and collagen to coat 4 mm ePTFE grafts with wall porosity of 20 xcexcm. Data from 30-day implantation in canine models were reported. The authors show that 88% of the surface was covered with endothelial cells and the patency was 88%. Guidoin and his coworkers, however, have shown that the healing response with collagen coatings changes significantly after 30 days, resulting in substantial thickening of the vessel wall despite the presence of a layer of endothelial cells on the luminal surface. Therefore, the presence of endothelial cell coverage cannot be taken as evidence that this method will yield grafts with improved long-term patency.
Another method for improving the patency of small diameter vascular grafts has been the use of Dacron scaffolds implanted in the cutaneous trunci muscle of sheep to grow ovine collagenous tissue around the graft. Such a technique was described by Werkmeister et al in Transactions, Society for Biomaterials, April 1994. The use of scaffolds to grow animal tissue for human implantation is prone to poor quality control and is often expensive. Yet another method for fabricating small diameter vascular grafts involves combining two different layers of collagenous material as described by Termin et al, Transactions, Society for Biomaterials, April 1994. It is well known that composites manufactured from biological sources and used as blood conduits are prone to degradation and failure from aneurysms. Therefore this method does not offer a viable solution either. It is well known to those skilled in the art, that materials derived from animal tissue are also prone to calcification, thus significantly reducing the effectiveness of devices fabricated from such sources.
In U.S. Pat. No. 4,842,575, herein incorporated by reference, synthetic vascular grafts are impregnated with collagen. As described in earlier references, the use of collagen impregnation does not lead to improved patency of small caliber vascular conduits. In U.S. Pat. Nos. 5,643,712 and 5,880,090, herein incorporated by reference, the grafts are seeded with endothelial cells. While such coating may offer improved resistance to thrombosis, such coatings have not reduced intimal hyperplasia and thus do not guarantee improved patency of these small caliber vascular conduits. In U.S. Pat. No. 5,851,229, herein incorporated by reference, the inventors describe a bio-resorbable sealant for porous vascular grafts. The material used is a water absorbing polymer called a hydrogel. While such a coating can provide sealing action, it does not necessarily provide the needed anti-thrombogenic behavior, nor do such coatings reduce smooth muscle cell proliferation and intimal hyperplasia.
Greisler et al, Biomaterials 1996, Vol. 17, No. 3, studied the effects of impregnating ePTFE grafts, which have porous walls, with a mixture of Fibrin Glue, Acidic Fibroblast Growth Factor, and heparin on endothelial growth and intimal hyperplasia. This mixture appears to allow proliferation of endothelial cells on the luminal surface and in the presence of high concentration of heparin, reduce smooth muscle cell proliferation by 12%. While this reduction in smooth muscle cell proliferation is significant, it is not entirely sufficient for long-term patency. Greisler et al, in Surfaces in Biomaterials Symposium 1994, also examined the wash out kinetics of this mixture using 125I labeled Acidic Fibroblast Growth Factor and found that 86% of the mixture was washed out from the graft within fourteen days. By the end of 30 days, 96% of the mixture had been washed out from the graft. Thus, the effect of this approach appears to decrease exponentially with elapsed time.
Therefore, what is needed is a small diameter vascular conduit with diameters xe2x89xa65 mm and which has (i) a luminal surface that is permanently non-thrombogenic, (ii) a graft structure such that smooth muscle proliferation and consequent intimal hyperplasia is substantially reduced or eliminated, and (iii) a graft structure that allows integration of the graft into the surrounding tissue.
The present invention substantially reduces or overcomes all of the problems associated with the prior art. The invention provides a novel multi-zone, multifunctional graft with two or more zones that have different chemical and biological characteristics. The present invention further provides a graft with these characteristics where the biological and chemical properties of the different zones are substantially independent of one another. The present invention further provides a vascular conduit that has of an inner zone that is permanently non-thrombogenic and anti-proliferative, and one or more outer zones that allow for beneficial tissue in-growth and sealing of the graft to prevent leakage. The small diameter vascular conduits of the present invention containing these different zones may be fabricated from woven or knitted Dacron, extruded porous PTFE, from polyurethane polymer, or other similar materials, and the structure of these conduits so modified as to provide these different zones. One embodiment contains an inner non-thrombogenic layer and an outer thrombogenic layer, optionally containing a growth agent. A second embodiment contains a third intermediate layer having a growth agent impregnated therein.